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RNA uridyl transferases TUT4/7 differentially regulate miRNA variants depending on the cancer cell type

Ragini Medhi1,2, Jonathan Price2, Giulia Furlan2

  • 1Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom.

RNA (New York, N.Y.)
|December 24, 2021
PubMed

Insights

Targeting terminal uridyl transferases TUT4/7 offers potential cancer therapy by disrupting miRNA uridylation, which affects cancer cell properties and gene expression. This study reveals cell-type-specific miRNA regulation by TUT4/7.

Area of Science:

  • * Molecular Biology
  • * Cancer Research
  • * RNA Biology

Background:

  • * Terminal uridyl transferases TUT4 and TUT7 (TUT4/7) add uridines to RNA 3' ends.
  • * TUT4/7, recruited by LIN28A, down-regulates tumor suppressor miRNA let-7, inhibiting tumorigenesis.
  • * Targeting TUT4/7 presents a potential anticancer therapy strategy.

Purpose of the Study:

  • * Investigate TUT4/7-mediated RNA regulation in cancer cell lines.
  • * Establish catalytic knockout models to study TUT4/7 function.
  • * Analyze the impact of TUT4/7 disruption on miRNA modification and cancer cell properties.

Main Methods:

  • * Creation of catalytic knockout models for TUT4/7 in cancer cell lines.
  • * Measurement of miRNA uridylation levels.
  • * Assessment of cancer cell proliferation and migration.
  • * Analysis of miRNA and mRNA expression profiles.
  • * Investigation of cell-type-specific miRNA regulation.

Main Results:

  • * TUT4/7 mutation significantly reduced miRNA uridylation.
  • * Loss of TUT4/7 activity impaired cancer cell proliferation and migration.
  • * Uridylated miRNA variants were replaced by adenylated isomiRs upon TUT4/7 loss.
  • * TUT4/7-mediated miRNA regulation is largely LIN28A-independent for most miRNAs.
  • * Identified cell-type-specific miRNA clusters regulated by TUT4/7, affecting mRNA targets like BCL2.
  • * miR-200c-3p and miR-141-3p expression are TUT4/7-regulated in a cancer-specific manner.

Conclusions:

  • * TUT4/7 loss leads to deregulation of miRNA-mRNA networks in a cell-type-specific manner.
  • * Understanding cell-type-specific deregulation is crucial for developing TUT4/7-targeted cancer therapies.
  • * Altered miRNA modification profiles, including isomiR changes, accompany expression deregulation.
Keywords:
LIN28ATUT4/7cancerisomiRslet-7miRNA–mRNA

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